Benzylphosphonic acid tyrosine kinase inhibitors

ABSTRACT

Certain benzylphosphonic acid compounds, and their pharmaceutically-acceptable salts, are inhibitors of tyrosine kinase enzymes, and so are useful for the control of tyrosine kinase dependent diseases (e.g., cancer, atherosclerosis).

TECHNICAL FIELD

This invention relates to acid compounds which are useful in the fieldof medicinal chemistry. More particularly the invention relates tobenzylphosphonic acid compounds which are tyrosine kinase inhibitorsuseful for the control of cancer, antiangiogenesis and atherosclerosis.

BACKGROUND OF THE INVENTION

Tyrosine-specific protein kinases (tyrosine kinases) represent a familyof enzymes which catalyze the transfer of the terminal phosphate ofadenosine triphosphate to tyrosine residues in protein substrates. Thefirst members of this class to be identified were tyrosine kinasesassociated with viral genes (termed oncogenes) which were capable ofcell transformation (i.e. pp60v-src and pp98v-fps). Later it was shownthat there were normal cellular counterparts (i.e. pp60c-src andpp98c-fps) to these viral gene products. A third category of tyrosinekinases to be identified are those termed the growth factor receptors,which includes insulin, epidermal growth factor, and p185HER-2receptors. All of these tyrosine kinases are believed, by way ofsubstrate phosphorylation, to play critical roles in signal transductionfor a number of cell functions.

Though the exact mechanisms of signal transduction have yet to beelucidated, tyrosine kinases have been shown to be importantcontributing factors in cell proliferation, carcinogenesis and celldifferentiation. Therefore, inhibitors of these tyrosine kinases areuseful for the prevention and chemotherapy of proliferative diseasesdependent on these enzymes.

SUMMARY OF THE INVENTION

This invention is directed to benzylphosphonic compounds that are usefulas tyrosine kinase inhibitors. The compounds of this invention have theformula ##STR1## and the pharmaceutically-acceptable cationic saltsthereof, in which A can be a wide variety of lipophilic groups which areneither strongly basic nor strongly acidic. Typical groups for A are-phenyl, -benzoyl, ##STR2## n=0 or 1. "Amine" represents the radicalNH-R, where NH₂ --R is an esterified derivative of a naturally-occurringamino acid. Representative groups of NH-R are ##STR3##

The present invention is also directed to pharmaceutical compositionsfor the control of tyrosine kinase dependent diseases in mammals whichcomprise a compound of the formula (I) in a pharmaceutically-acceptablecarrier; and to a method of controlling tyrosine kinase dependentdiseases which comprises administering to a mammal suffering fromtyrosine kinase dependent diseases a tyrosine kinase dependent diseasecontrolling amount of a compound of the formula (I).

The expression "pharmaceutically-acceptable cationic salt" refers tonontoxic cationic salts such as (but not limited to) sodium, potassium,calcium, magnesium, ammonium or protonated benzathine(N,N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine,ethylenediamine, meglamine (N-methylglucamine), benethamine(N-benzylphenethylamine), piperazine or tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol).

Other features and advantages will be apparent from the specificationand claims.

DETAILED DESCRIPTION OF THE INVENTION

In general, the phosphonic acid compounds of this invention of formula Ican be prepared by reacting the appropriate benzyl halide of formula IIwith a phosphite (the Arbusov reaction), followed by hydrolysis, asfollows ##STR4## These reactions are carried out by standard methods,well-known in the art.

Reaction of the benzyl halide of formula II with the phosphite isusually carried out by heating with a phosphite at temperatures of aboutambient (25° C.) to about 150° C., preferably about 60° C. to about 90°C., for about one to about 24 hours. Typically an excess of phosphite(e.g., 1.2 equivalents to about 10 equivalents) is used. The reactionmay be run neat (typically with at least about a 5 equivalent excess ofphosphite) or may be run in nonhydroxylic solvents such as nonpolarhydrocarbon solvents, ethereal solvents, etc. Specific examples includeTHF, DMF and toluene. Typically the reaction is run at ambient pressurealthough any pressure that does not adversely affect the desired endproduct may be used. A number of phosphite compounds can be used.However, particularly suitable are phosphite esters such as triethylphosphite or tristrimethylsilylphosphite.

The manner of carrying out the hydrolysis step depends to some extent onthe nature of the ester (i.e., the nature of the group R¹). For example,when a triethyl phosphite is used (i.e., R¹ is ethyl), the benzylphosphonic ester is heated (e.g., refluxed) with a concentrated mineralacid such as hydrochloric acid for about 12 to about 36 hours. Typicallythe hydrolysis is performed in the absence of a solvent (except for theacid). The reaction is conveniently performed at ambient pressurealthough any pressure that does not deleteriously affect the desired endproduct may be used.

When a trialkylsilyl ester is used, milder hydrolysis conditions such asstirring at about 0° C. to about 50° C. for about 2 to about 12 hours ina water miscible solvent such as THF, acetone or alcohols aresufficient. Water, typically about 5% to about 30% by volume of solvent,is used to effect the hydrolysis. Although any pressure that does notdeleteriously affect the desired end product may be used, the reactionis conveniently carried out at ambient pressure. The intermediatephosphonate ester of formula II can be isolated and purified, ifdesired. Alternatively, the intermediate ester can be hydrolysed insitu.

The phosphonic acids of formula I can be isolated and purified bystandard methods. For example, standard recrystallization orchromatograph procedures may be used; however, recrystallization ispreferred.

The starting halides of formula II can be made by a number of methods.The method will tend to vary somewhat, depending on the particular valueof the A group, but an appropriate method will be selected readily byone skilled in the art. For example, some of the benzyl halides of theformula II of this invention may be made by benzylic bromination, asdescribed empirically below, of the appropriate toluene-based startingcompound (IV) appropriately substituted to achieve the desired Afunctionality. ##STR5## Preferably the benzyl compound (IV) is reactedwith a brominating agent such as N-bromosuccinimide in the presence of aperoxide such as benzoyl peroxide in a aprotic solvent such as carbontetrachloride at reflux to produce the benzyl bromide (V).

Some of the starting compounds for the benzylic bromination may be madeby making the acid chloride of the appropriate acid (e.g.,dihydrocitrazinic acid), preferably by refluxing with thionyl chloride.The acid chloride is esterified by reaction with the paramethylphenol toyield the desired toluene-based starting compounds.

Other starting compounds for the benzylic bromination may be made bybasic treatment of paramethylphenol. Preferably, the paramethylphenol isreacted with potassium hydroxide in alcohol at room temperature, toyield the phenoxide followed by reaction with the appropriate methyltosylate and potassium iodide at about 150° C. to yield the desiredtoluene based starting compound.

For compounds that can't employ a benzylic halogenation an alternativesynthetic route, as depicted empirically below, is to condense an acidchloride (VI) (having a benzyl halide in the para position) with anappropriate amine or alcohol to yield an amide or ester (VII). ##STR6##n=1, 2 or 3, H-Nucleophile=amine or alcohol.

Preferably, the acyl halide is reacted with an amine or alcohol undernitrogen at about 0° C. to about 25° C. in the presence of a base suchas triethylamine and an aprotic solvent such as methylene chloride. Theresulting amide or ester can then be condensed with a phosphite asdescribed above.

The starting benzyl chlorides used in the above reaction sequence may beformed by bromomethylation and conversion to the acylchloride (X) asdescribed empirically below, of the appropriate acid (VIII). ##STR7##Preferably 3-phenylpropionic acid is heated with paraformaldehyde andHBr at about 25° C. to about 100° C. Preferably the acid (IX) is reactedwith oxalylchloride under nitrogen at ambient temperature.

Yet other benzyl phosphonic acid based compounds can be prepared bycondensing the appropriate hydantoin (XI) with bis-benzyl halides (XII)as described empirically below. ##STR8## wherein R² is a lipophilicconstituent such as phenyl and X is halogen (i.e., chlorine, bromine,iodine or fluorine). Preferably an N-3 protected hydantoin is treatedwith a base such as magnesium methoxycarbonate at temperatures fromabout 25° C. to about 120° C. in an aprotic solvent followed bytreatment with a dihalide at a similar temperature.

The hydantoin starting compounds (XI) may be made by reaction of anamine with ethyl isocyanatoacetate followed by treatment with acid.

The starting materials for the above described three major reactionpathways, benzylic halogenation, condensation of acid chloride withamine or alcohol and condensation of bis-benzyl halides with hydantoins,can be easily synthesized by those skilled in the art starting fromcommon chemical reagents using conventional methods of organicsynthesis.

The compounds of this invention are acidic and they form base salts. Allsuch base salts are within the scope of this invention and they can beprepared by conventional methods. For example, they can be preparedsimply by contacting the acidic and basic entities, usually in astoichiometric ratio, in either an aqueous, non-aqueous or partiallyaqueous medium, as appropriate. The salts are recovered either byfiltration, by precipitation with a non-solvent followed by filtration,by evaporation of the solvent, or, in the case of aqueous solutions, bylyophilization, as appropriate.

The compounds of this invention are all readily adapted to therapeuticuse as tyrosine kinase inhibitors for the control of tyrosine kinasedependent diseases in mammals. Tyrosine kinase dependent diseases referto hyperproliferative disorders which are initiated/maintained byaberrant tyrosine kinase enzyme activity. Examples include cancer,atherosclerosis, antiangiogenersis (e.g., tumor growth, diabeticretinopathy), etc.

The compounds are administered either orally or parenterally, ortopically as eye drops, in dosages ranging from about 0.1 to 10 mg/kg ofbody weight per day in single or divided doses. Of course, in particularsituations, at the discretion of the attending physician, doses outsideof this range will be used.

The compounds of this invention can be administered in a wide variety ofdifferent dosage forms, i.e., they may be combined with variouspharmaceutically-acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, powders, sprays, elixirs,syrups, injectable or eye drop solutions, and the like. Such carriersinclude solid diluents or fillers, sterile aqueous media and variousnon-toxic organic solvents.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate are employed along with various disintegrants such as starchand preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the essential active ingredient therein can be combinedwith various sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as well as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble, alkali metal oralkaline-earth metal salts previously enumerated. Such aqueous solutionsshould be suitable buffered, if necessary, and the liquid diluent firstrendered isotonic with sufficient saline or glucose. These particularaqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal injection purposes. Inthis connection, the sterile aqueous media employed are all readilyobtainable by standard techniques well-known to those skilled in theart.

For purposes of topical administration, dilute sterile, aqueoussolutions (usually in about 0.1% to 5% concentration), otherwise similarto the above parenteral solutions, are prepared in containers suitablefor dropwise administration to the eye.

In a pharmaceutical composition comprising a compound of formula I, or apharmaceutically-acceptable salt thereof, the weight ratio of carrier toactive ingredient will normally be in the range from 1:4 to 4:1, andpreferably 1:2 to 2:1. However, in any given case, the ratio chosen willdepend on such factors as the solubility of the active component, thedosage contemplated and the precise route of administration.

It should be understood that the invention is not limited to theparticular embodiments shown and described herein, but that variouschanges and modifications may be made without departing from the spiritand scope of this novel concept as defined by the following claims.

EXAMPLE 1 1. 4-benzoylbenzyl bromide

To a solution of 4.0 g (20 mmol) of 4-benzoyltoluene and 3.6 g (20 mmol)of N-bromosuccinimide in 120 ml of carbon tetrachloride was added 0.05 g(0.2 mmol) of benzoyl peroxide. The reaction was refluxed for 17 hours,cooled to room temperature and filtered. The filtrate was evaporated andthe crude product was taken on without further purification.

2. 4-benzoylbenzylphosphonic acid

A mixture of 4.8 g of 4-benzoylbenzyl bromide and triethylphosphite washeated at 125° C. for 0.5 hours and cooled to room temperature. Theresulting oil was purified by flash chromatography (70% ethylacetate/hexanes) to afford 3.2 g of diethyl 4-benzoylbenzylphosphonicacid, as an oil. A mixture of 3.2 g (9.6 mmol) of diethyl4-benzoylbenzylphosphonic acid and 40 ml of concentrated hydrochloricacid was refluxed for 7 hours and cooled to room temperature. The twophase mixture was partitioned between 125 ml of water and 400 ml ofEtOAc, the EtOAc layer was dried over Na₂ SO₄, filtered and evaporatedto give 0.7 g of product; m.p. 172°-175° C.

Analysis calculated for C₁₄ H₁₃ O₄ P: C, 60.87; H, 4.74%. Found: C,60.94; H, 4.66%.

EXAMPLE 2 1. 4-(Phenylsulfonyl)benzyl bromide was prepared from4-(phenylsulfonyl)toluene according to Example 1, part 1. 2.4-(phenylsulfonyl)benzylphosphonic acid

A solution of 4.3 g (14 mmol) of 4-(phenylsulfonyl)benzyl bromide and 30g (0.1 mole) of tris-trimethylsilylphosphite was heated at 120° C. for18 hours. The excess tris-trimethylsilylphosphite was distilled offunder reduced pressure. The residue was dissolved in 200 ml of 9:1tetrahydrofuran/water and was allowed to stand at room temperature for18 hours. The tetrahydrofuran was evaporated and the resulting solidswere filtered and washed with water to give 1.4 g of product; m.p.217-219° C.

Analysis calculated for C₁₃ H₁₃ O₅ PS: C, 50.00; H, 4.20%. Found: C,50.00; H, 4.14%.

EXAMPLE 3 1. N-[4(bromomethyl)phenyl]phthalimide

The title compound was prepared from N-[4(methyl)phenyl]phthalimideaccording to the procedure of Example 1, part 1.

2. 4-(N-phthalimidyl)benzylphosphonic acid

The title compound was prepared from N-[4(bromomethyl)phenyl]phthalimideaccording to the procedure of Example 2, part 2; m.p. 239°-243° C.

Analysis calculated for C₁₅ H₁₂ NO₅ P: C, 56.79; H, 3.81; N, 4.42%.Found: C, 57.04; H, 3.74; N, 4.45%.

EXAMPLE 4 1. 4-[((1-methyl)cyclohexyl)methoxy]toluene

To a cooled (0° C.), stirred solution of 8.4 g (0.15 mole) of potassiumhydroxide in 100 ml of MeOH was added 13.5 g (0.12 mole) of4-methylphenol over a 15 minute period. The reaction was stirred at roomtemperature for 0.5 hour and MeOH was evaporated to afford a solid. Asolution of this solid, 28.2 g (0.1 mole) of((1-methyl)cyclohexyl)methyl tosylate and 1.4 g of potassium iodide wereheated at 150° C. for 5 hours. The reaction was cooled to roomtemperature, poured onto ice-water and extracted with EtOAc. The EtOAclayer was washed with 2N aqueous NaOH, brine, dried over MgSO₄, filteredand evaporated. The resulting oil was filtered through a plug of silicagel to give 20 g of product as an oil.

2. 4-[((1-methyl)cyclohexyl)methoxy]benzyl bromide

A solution of 2.2 g (10 mmol) of4-[((1-methyl)cyclohexyl)methoxy]toluene, 1.8 g (10 mmol) ofN-bromosuccinimide and 0.02 g of benzoyl peroxide in 60 ml of carbontetrachloride was refluxed for 16 hours. The reaction was cooled to roomtemperature, filtered and the filtrate evaporated to give the productwhich was used without further purification.

3. diethyl 4-[((1-methyl)cyclohexyl)methoxy]benzylphosphonate

A mixture of the 4-[((1-methyl)cyclohexyl)methoxy]benzyl bromide and 1.7g (10 mmol) of triethylphosphite was heated at 145° C. for 0.2 hour. Thereaction was cooled to room temperature and flash chromatographed togive 1.3 g of product as an oil.

4. 4-[((1-methyl)cyclohexyl)methoxy]benzylphosphonic acid

A solution 0.7 g (2.0 mmol) of diethyl4-[((1methyl)cyclohexyl)methoxy]benzylphosphonate and 10 ml ofconcentrated hydrochloric acid was refluxed for 24 hours. The reactionwas cooled to room temperature, filtered and the solids were washed withwater. The solids were recrystallized from EtOAc/cyclohexane to give 0.4g of the product; m.p. 170°-172° C.

Analysis calculated for C₁₅ H₂₃ O₄ P: C, 60.39; H, 7.77%. Found: C,60.73; H, 7.87%.

EXAMPLE 5 1. 4-(4-methylphenoxy)carboxyglutarimide

A solution of 46 g (0.3 mole) of dihydrocitrazinic acid in 350 ml ofthionyl chloride was refluxed for 6 hours, cooled to room temperatureand evaporated to dryness. The resulting solids were recrystallized frombenzene to give 33 g of dihydrocitrazinoyl chloride; m.p. 120°-121.5° C.A solution of 6.0 g (34 mmol) of dihydrocitrazinoyl chloride, 3.7 g (34mmol) of 4-methylphenol and 3 ml of pyridine in 60 ml of p-dioxane wasrefluxed for 2 hours. The upper layer was separated, cooled to roomtemperature and the solids were isolated by filtration. The solids wererecrystallized from acetone to give 1.2 g of product; m.p. 183°-184° C.

Analysis calculated for C₁₃ H₁₃ NO₄ : C, 63.15; H, 5.66; N, 5.26%.Found: C, 63.22; H, 5.74; N, 5.47%.

2. 4-[4-(bromomethyl)phenoxy]carboxyglutarimide

A solution of 1.3 g (5.2 mmol) of 4-(4-methylphenoxy)carboxyglutarimide,1.0 g (5.7 mmol) of N-bromosuccinimide and 0.02 g of benzoyl peroxide in30 ml of carbon tetrachloride was refluxed for 16 hours, cooled to roomtemperature, evaporated and the residue dissolved in 200 ml of ethylacetate. The EtOAc layer was washed with water, dried over Na₂ SO₄ andevaporated to give 1.6 g of the crude product.

3. 4-[(4-methylphosphonic acid)phenoxy]carboxyglutarimide

The titled compound was prepared from4-[4-(bromomethyl)phenoxy]carboxyglutarimide according to Example 2,part 2; m.p. 242°-244° C.

Analysis calculated for C₁₃ H₁₄ NO₇ P: C, 47.71; H, 4.31; N, 4.28%.Found: C, 47.53; H, 4.22; N, 4.30%.

EXAMPLE 6 1. benzyl 4-(chloromethyl)benzoic acid

A stirred suspension of 3.0 g (14 mmol) of 4-(bromomethyl)benzoic acidand 3.5 ml (41 mmol) of oxalyl chloride in 35 ml of dichloromethane wasrefluxed for 10 hours and cooled to room temperature. Evaporationafforded 4-(chloromethyl)benzoyl chloride as an oil which was usedwithout purification. To a cooled (0° C.) solution of 2.6 g (14 mmol) of4-(chloromethyl)benzoyl chloride and 2.0 g (18 mmol) of benzyl alcoholin 30 ml of dichloromethane was added 1.8 g (18 mmol) of triethylamine.The reaction was stirred at 0° C. for 0.2 hours, then at roomtemperature for an additional 1 hour and poured into 150 ml of EtOAc.The EtOAc layer was with three portions of water, dried over Na₂ SO₄,filtered and evaporated. The crude product was flash chromatographed (5%EtOAc/hexanes) to give 0.7 g of product; m.p. 52°-54° C.

2. benzyl 4-(methylphosphonic acid)benzoic acid

The titled compound was prepared from benzyl 4-(chloromethyl)benzoicacid according to the procedure of Example 2, part 2; m.p. 160°-163° C.

EXAMPLE 7 1. 3-[4-(chloromethyl)phenyl]propionyl chloride

A solution of 1.5 g (6.2 mmol) of 3-[4-(bromomethyl)phenyl]propionicacid (U.S. Pat. No. 4,032,533) and 1.2 g (9.3 mmol) of oxalyl chloridein 6 ml of dichloromethane was stirred at room temperature for 2.5 hoursand evaporated to give 1.6 g of product as an oil.

2. N-[3-(4-(chloromethyl)phenyl)propionyl]phenylalanine, methyl ester

To a cooled (0° C.), stirred solution of 1.6 g (6.2 mmol) of3-[4-(chloromethyl)phenyl]propionyl chloride and 1.3 g (6.2 mmol) ofphenylalanine methyl ester hydrochloride salt in 6 ml of dichloromethanewas added 1.4 g (14 mmol) of triethylamine. The reaction mixture wasstirred at 0° C. for 0.5 hour, poured into EtOAc and washed with water.The EtOAc layer was dried over Na₂ SO₄, filtered and evaporated toafford an oil. This oil was flash chromatographed (40% EtOAc/hexanes) togive 0.8 g of product; m.p. 89°-90° C.

Analysis calculated for C₂₀ H₂₂ ClNO₃ : C, 66.66; H, 6.15; N, 3.88%.Found: C, 66.85; H, 6.19; N, 3.69%.

3. N-[3-(4-(methylphosphonic acid)phenyl)propionyl]phenylalanine methylester

The titled compound was prepared fromN-[3-(4-(chloromethyl)phenyl)propionyl]phenylalanine methyl esteraccording to the procedure of Example 2, part 2; m.p. 139°-142° C.

Analysis calculated for C₂₀ H₂₄ NO₆ P: C, 59.26; H, 5.97; N, 3.46%.Found: C, 58.97; H, 5.85; N, 3.43%.

EXAMPLE 8 1.N-ε-carboxybenzyloxy-N-[3-(4-(chloromethyl)phenyl)propionyl]lysine,methyl ester

To a cooled, (0° C.), stirred slurry of 1.6 g (6.2 mmol) of3-[4-(chloromethyl)phenyl]propionyl chloride and 2.0 g (6.2 mmol) ofN-ε-carboxybenzyloxylysine methyl ester hydrochloride salt in 6 ml ofdichloromethane was added 1.4 g (14 mmol) of triethylamine. The reactionwas stirred at room temperature for 2 hours, poured into EtOAc andwashed with water. The EtOAc layer was dried over Na₂ SO₄, filtered andevaporated to afford an oil. This oil was flash chromatographed (55%EtOAc/hexanes) to give 2.1 g of product; m.p. 98°-101° C.

Analysis calculated for C₂₅ H₃₁ ClN₂ O₅ : C, 63.21; H, 6.58; N, 5.90%.Found: C, 63.47; H, 6.59; N, 6.02%.

2. N-ε-carboxybenzyloxy-N-[3-(4-methylphosphonicacid)phenyl)propionyl]lysine, methyl ester

The titled compound was made from the above product using the procedurein Example 2, part 2; m.p. 83° C.

Analysis calculated for C₂₅ H₃₃ N₂ O₈ P·1/2H₂ O: C, 56.71; H, 6.47; N,5.29%. Found: C, 56.56; H, 6.21; N, 5.36%.

3. N-[3-(4-(methylphosphonic acid)phenyl)propionyl] lysine, methyl ester

A slurry of 0.63 g (1.2 mmol) ofN-ε-carboxybenzyloxy-N-[3-(4-(methylphosphonicacid)phenyl)propionyl]lysine, methyl ester and 0.5 g of 10% palladium oncarbon in 17 ml of MeOH was subjected to 30 psi hydrogen for 4.5 hours.Evaporation of MeOH afforded a mass which was continuously extractedwith hot MeOH for 72 hours. Evaporation afforded a solid which wasdissolved in 40 ml of hot water, filtered and the filtrate wasevaporated to give 136 mg of product; m.p. 262°-264° C.

Analysis calculated for C₁₇ H₂₇ N₂ O₆ P·1/3H₂ O: C, 52.04; H, 7.11; N,7.14%. Found: C, 52.11; H, 6.93; N, 6.99%.

EXAMPLE 9 1. ethyl δ-phenyl hydantoate

To a cooled (0° C.), stirred solution of 6.5 g (50 mmol) of ethylisocyanatoacetate in 75 ml of ethyl ether was added a solution of 4.7 g(50 mmol) of aniline in 50 ml of ethyl ether. The reaction was warmed toroom temperature, stirred for 0.5 hour, evaporated to two-thirds theoriginal volume, cooled to 0° C. and filtered to give 8.2 g of product;m.p. 110°-111° C.

2. 3-phenylhydantoin

A solution of 5.6 g (25 mmol) of ethyl δ-phenyl hydantoate in 25 ml of6N hydrochloric acid was heated at 100° C. for 1 hour and then cooled to0° C., Filtration gave 3.6 g of product; m.p, 154°-156° C.

3. 4-(4-chloromethylbenzyl)-3-phenyhydantoin

To 8.8 ml of a 2M solution of magnesium methyl carbonate indimethylformamide was added 0.9 g (5.0 mmol) of 3-phenylhydantoin andthe resulting mixture was heated at 90° C. for 0.5 hour. To the reactionwas added 8.8 g (50 mmol) of 4-(chloromethyl)benzyl chloride and thereaction was maintained at 90° C. for 0.5 hour. The reaction was pouredonto 75 g of ice, 15 ml of 1N hydrochloric acid added and the resultingmixture stirred for 0.2 hour. The reaction was extracted with 250 ml ofEtOAc, the organic layer was washed with water, dried over Na₂ SO₄,filtered and evaporated to give a solid. This solid was flashchromatographed (60% EtOAc/hexanes) to give 1.2 g of product; m.p.167°-168° C.

Analysis calculated for C₁₇ H₁₅ ClN₂ O₂ : C, 64.86; H, 4.80; N, 8.90%.Found: C, 64.76; H, 4.78; N, 8.75%.

4. 4-[(4-methylphosphonic acid)benzyl]-3-phenylhydantoin

The titled compound was made from the above product using the procedureof Example 2, part 2; m.p. 190°-192° C.

Analysis calculated for C₁₇ H₁₇ N₂ O₅ P: C, 56.34; H, 4.76; N, 7.78%.Found: C, 56.34; H, 4.66; N, 7.76%.

EXAMPLE 10 1. diethyl 4-phenylbenzylphosphonate

A stirred mixture of 5.0 g (20 mmol) of commercially available4-bromomethyldiphenyl and 4.4 g (26 mmol) of triethylphosphite washeated at 120° C. for 3 hours and then allowed to cool to roomtemperature. The resulting oil was purified by flash chromatography (500g 60% EtOAc/hexanes) to give 5.4 g of product; m.p. 55°-58° C.

Analysis calculated for C₁₇ H₂₁ O₃ P: C, 67.09; H, 6.96%. Found: C,66.85; H, 6.97%.

2. 4-phenylbenzylphosphonic acid

A vigorously stirred suspension of 3.5 g (12 mmol) of diethyl4-phenylbenzylphosphonate in 35 ml of concentrated hydrochloric acid wasrefluxed for 45 hours and cooled to room temperature. The solids werefiltered, washed with water and then recrystallized from EtOH to give0.5 g of product; m.p. 246°-248° C.

Analysis calculated for C₁₃ H₁₃ O₃ P: C, 62.90; H, 5.28%. Found: C,62.86; H, 5.22%.

EXAMPLE 11 4-(phenylsulfonylmethyl)benzylphosphonic acid

Commercially available 4-(phenylsulfonylmethyl)benzyl bromide wasconverted according to the procedure of Example 2, part 2 to4-(phenylsulfonylmethyl)benzylphosphonic acid; m.p. >280° C.

Analysis calculated for C₁₄ H₁₅ O₅ PS: C, 51.53; H, 4.63%. Found: C,51.65; H, 4.61%.

We claim:
 1. A compound of the formula ##STR9## wherein A is, ##STR10##and the pharmaceutically-acceptable cationic salts thereof.
 2. Acompound of claim 1, wherein A is ##STR11##
 3. A compound of claim 1,wherein A is ##STR12##
 4. A compound of claim 1, wherein A is ##STR13##5. A compound of claim 1, wherein A is ##STR14##
 6. A pharmaceuticalcomposition for the control of tyrosine kinase dependent diseases inmammals which comprises a compound of claim 1 in apharmaceutically-acceptable carrier.
 7. A method of controlling tyrosinekinase dependent diseases which comprises administering to a mammalsuffering from tyrosine kinase dependent diseases a tyrosine kinasedependent disease controlling amount of a compound of claim 1.